UPREGULATED ARACHIDONIC ACID DUE TO DEFICIENT SEROTONIN REUPTAKE TRANSPORTER. Humans carrying the short (S) compared with the long (L) allele of the presynaptic serotonin reuptake transporter (5-HTT) promoter have increased extracellular serotonin (5-HT) and are at increased risks for neuropsychiatric diseases including BD. The heterozygous 5-HTT knockout mouse (5-HTT-/+), also has elevated synaptic 5-HT and shows depressive-like behaviors. It is considered a model for humans carrying the S promoter allele of the 5-HTT. We demonstrated 20-70% increases in baseline AA incorporation from plasma into different brain regions, in 5-HTT-/+ and homozygous 5-HTT-/- mice compared with wild type 5-HTT+/+ mice. The knockout mice had an elevated brain cytosolic phospholipase A2(cPLA2) activity, which we interpreted as a response to tonic stimulation of cPLA2-coupled 5-HT2A/2C receptors. Behavioral and AA signaling responses in the 5-HTT knockouts to the 5-HT2A/2C agonist, (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), were consistent with DOI's function as a partial agonist. Thus, reduced 5-HTT function during neurodevelopment produces abnormal AA signaling and behavior during adulthood in the mouse (Ref. 1). ACUTE BUT NOT CHRONIC DONEPEZIL ADMINISTRATION INCREASES MUSCARINIC RECEPTOR-MEDIATED BRAIN SIGNALING INVOLVING ARACHIDONIC ACID IN UNANESTHETIZED RATS. Memory changes in Alzheimer disease have been ascribed to a deficit in cholinergic transmission. Donepezil, an acetylcholinesterase (AChE) inhibitor, is used to treat the disease. It is thought to act by increasing synaptic acetylcholine (ACh), thus stimulating post-synaptic muscarinic M1,3,5 receptors that can be coupled to cPLA2 and (AA) release. However, some clinical trials indicate no significant Donepezil effect on Alzheimer disease progression. We found that the AA signaling response to Donepezil in awake rats showed desensitization, which may explain why Donepezil may not affect Alzheimer disease progression. Clinical trials with direct M1,3,5 agonists may still be worthwhile (Ref. 2). CHRONIC D-AMPHETAMINE DEPRESSES AN IMAGING MARKER OF ARACHIDONIC ACID METABOLISM IN RAT BRAIN. Withdrawal from psychostimulants such as amphetamine and cocaine, which inhibit or reverse the synaptic dopamine reuptake transporter, often causes depression. Rats at 1 day after withdrawal from chronic amphetamine showed reduced baseline (AA) incorporation into the nucleus accumbens and striatum, and reduced AA responses to the D2-like receptor agonist, quinpirole. These reductions may underlie post-depression following amphetamine addiction, which has been reported in rats and humans (Ref. 3). APOMORPHINE STIMULATES ARACHIDONIC ACID SIGNALING VIA DOPAMINE D2-LIKE RECEPTORS. Apomorphine, a mixed dopamine D1/D2 receptor agonist, is used to treat patients with Parkinson disease. In awake rats, acute apomorphine provoked a robust (AA) signal in brain regions with dopamine receptors solely through the D2 receptors, as the signal could be blocked by pre-administration of raclopride, a D2/D3 receptor antagonist (Ref. 4) This study supports our approved clinical protocol in which apomorphine is injected to image dopamine signaling with positron emission tomography (Ref. 4). ACUTE NICOTINE REDUCES BRAIN ARACHIDONIC ACID SIGNALING IN UNANESTHETIZED RATS. Nicotine can improve memory and attention, but is highly addictive. In brain, it binds primarily to the common high-affinity presynaptic cholinergic alpha4beta2 receptors, which modulate release of other neurotransmitters that can activate post-synaptic receptors coupled to cPLA2. Alpha4beta2 receptors undergo desensitization within 10-15 min, which may be related to nicotine addiction. We also demonstrated desensitization of signaling in vivo. Nicotine at a dose equivalent to smoking 1 cigarette (0.1 mg/kg, s.c.), compared to saline, decreased the arachidonic acid (AA) signal in rat brain at 2 min but not at 10 min after injection, consistent with rapid desensitization. The 2 min signal was blocked by the alpha4beta2 antagonist mecamylamine (Ref. 5). INTRACELLULAR- AND EXTRACELLULAR-DERIVED CALCIUM INFLUENCE PHOSPHOLIPASE A2-MEDIATED FATTY ACID RELEASE FROM BRAIN PHOSPHOLIPIDS. We wrote a critical review regarding regulation by calcium-independent PLA2 (iPLA2) release of the n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA, 22:6n-3), from membrane phospholipid during neurotransmission. We indicated that while DHA is not likely released when extracellular calcium is allowed into the cell through ionotropic neuroreceptors, it should be released following activation of G-protein coupled receptors secondary to calcium release from the intracellular endoplasmic reticulum (Ref. 6).